An Open, Dose-escalation, Phase 1b Clinical Trial to Evaluate the Safety and Efficacy of EN001 in Patients with Charcot-Marie-Tooth Disease type 1A (CMT1A)
This clinical trial is a phase 1b clinical trial with a 3+3 dose escalation design to evaluate the safety, including tolerability, of EN001 and explore efficacy. The study was designed using the traditional 3+3 dose escalation method to confirm the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D). Dose increase is carried out until the maximum tolerated dose (MTD) is confirmed at a dose of 2.5 × 10\^6 cells/kg (Cohort 2) or less, which is the maximum planned dose (MPD). The maximum tolerated dose (MTD) is defined as the highest dose at which the incidence of dose limiting toxicity (DLT) is lower than 33%. To determine the maximum tolerated dose (MTD), 3-6 test subjects from each dose cohort are enrolled and EN001 is administered twice at 4-week intervals, and dose-limiting toxicity (DLT) is evaluated until 4 weeks (visit 6). The safety review committee (SRC) is comprised of the principal investigator, sponsor, etc. as members, and EN001 confirmed by the end of each cohort (end of dose-limiting toxicity (DLT) evaluation of the last dosed subject in the cohort). Safety data are comprehensively reviewed to determine all matters related to dose, such as increase or decrease in dose, and finally the recommended phase 2 dose (RP2D) is determined. In addition, test subjects participating in phase 1b will be followed up for safety and effectiveness for 5 years from the time of EN001 administration according to the long-term follow-up protocol.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
* Cohort 1: EN001 1.25×10\^6 cells/kg administered intravenously (IV) 2 times at 4 week intervals. * Cohort 2: EN001 2.5×10\^6 cells/kg administered intravenously (IV) 2 times at 4 week intervals.
Samsung Medical Center
Seoul, South Korea
Dose limiting toxicity (DLT) and adverse drug reactions related to discontinuation of investigational product administration
Present the frequency and percentage of dose-limiting toxicity (DLT) occurrence across dose cohorts, along with detailed information on the types of DLTs. Adverse events related to discontinuation of clinical investigational drug administration, discontinuation of clinical investigational drug administration Regarding related adverse drug reactions, the number of subjects in each cohort, incidence rate (%), and Two-sided 95% confidence intervals and number of occurrences are presented.
Time frame: Up to 8 weeks
CMTNSv2 score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
CMT examination score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Rasch-modified CMTNSv2 score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Rasch-modified CMTES score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
FDS score change
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Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
ONLS score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
10MWT score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Change in grade of fatty infiltration in the proximal lower extremities (According to Goutallier classification scale)
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 24 weeks compared to baseline (Visit 2)
Change in Motor Nerve Conduction Velocity (Unit: m/s)
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Change in Compound Muscle Action Potential (Unit: ㎷)
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Change in Sensory Nerve Action Potential (Unit: ㎶)
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
Change in Sensory Nerve Conduction Velocity (Unit: m/s)
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 4, 8, 18, and 24 weeks compared to baseline (Visit 2)
SF-36v2 score change
Present the subject count, mean, standard deviation, median, minimum, and maximum for the changes at each time point within each dosage group.
Time frame: At 24 weeks compared to baseline (Visit 2)
Adverse Event
By cohort that Number of subjects, incidence rate (%), confidence interval (two-sided 95%), presents the number of occurrences. Additional, The pre-treatment adverse event that occurred before administration of clinical trial drugs is presented in detail.
Time frame: Up to 24weeks. However, adverse drug reactions that persist at the end of the clinical trial will be followed up until the possible adverse reactions are resolved or it is determined that further follow-up is not meaningful.
Vital sign
Number of participants with clinically significant abnomalities in vital signs after EN001 administration. Vital Signs include blood pressure (mmHg), pulse (times/minute), respiratory rate (times/minute), and body temperature (℃) and will be assessed. By cohort and visit, present continuous variables with subject count, mean, standard deviation, median, minimum, and maximum. For categorical variables, provide shift table.
Time frame: Up to 24 weeks
Laboratory examination
Number of participants with clinically significant abnormalities in Laboratory parameters after EN001 administration. Hematological tests, Blood chemical tests, Blood coagulation test, Urine test, Serum virus test. It is conducted through blood and urine collection, and the PI checks whether the test results are normal, abnormal, and clinically significant.
Time frame: Up to 24 week. Serum virus testing is performed only during screening. At Baseline and Week 4, hematological tests, blood chemical tests, TCO2, Mg, and blood coagulation tests are performed before and within 4 hours after administration of the IP.
electrocardiography
Number of participants with clinically significant abnormalities in electrocardiography after EN001 administration. Based on the PR Interval, QRS Duration, QTc Interval and QTcF Interval, PI checks whether the test results are normal, abnormal, and clinically significant. by cohort and visit, present continuous variables with subject count, mean, standard deviation, median, minimum, and maximum. For categorical variables, provide shift table.
Time frame: At Baseline, Week 4, Week 8, Week 12, Week 18, Week 24
X-ray
by cohort and visit, present continuous variables with subject count, mean, standard deviation, median, minimum, and maximum. For categorical variables, provide shift table.
Time frame: Before administration of investigational product at Baseline and Week 4 and within 4 hours after completion of administration
Physical Examinations
Number of participants with clinically significant abnormalities in Physical Examinations after EN001 administration. Based on general appearance, head, ears/eyes/nose/throat, cardiovascular, respiratory, abdomen, skin, lymph nodes, extremities, musculoskeletal and neurologic, PI checks whether the test results are normal, abnormal, and clinically significant. By cohort and visit, present continuous variables with subject count, mean, standard deviation, median, minimum, and maximum. For categorical variables, provide shift table.
Time frame: Up to 24 weeks